In Silico Characterization and Homology Modeling of a Cyanobacterial Phosphoenolpyruvate Carboxykinase Enzyme

ATP-dependent phosphoenolpyruvate carboxykinase (PEPCK) is a key catabolic enzyme found in various species of bacteria, plants, and yeast. PEPCK may play a role in carbon fixation in aquatic ecosystems consisting of photosynthetic cyanobacteria. RuBisCO-based CO2 fixation is prevalent in cyanobacteria through C3 intermediates; however, a significant amount of carbon flows into C4 acids during cyanobacterial photosynthesis. This indicates that a C4 mechanism for inorganic carbon fixation is prevalent in cyanobacteria with PEPCK as an important β-carboxylation enzyme. Newly available genomic information has confirmed the existence of putative PEPCK genes in a number of cyanobacterial species. This project represents the first structural and physicochemical study of cyanobacterial PEPCKs. Biocomputational analyses of cyanobacterial PEPCKs were performed and a homology model of Cyanothece sp. PCC 7424 PEPCK was generated. The modeled enzyme consists of an N-terminal and C-terminal domains with a mixed α/β topology with the active site located in a deep cleft between the two domains. Active site residues and those involved in metal ion coordination were found to be conserved in the cyanobacterial enzymes. An active site lid which is known to close upon substrate binding was also predicted. Amino acid stretches that are unique to cyanobacterial PEPCKs were also identified.

Structure Topology Prediction of Discriminative Sequence Motifs in Membrane Proteins with Domains of Unknown Functions

Motivation. Membrane proteins play essential roles in cellular processes of organisms. Photosynthesis, transport of ions and small molecules, signal transduction, and light harvesting are examples of processes which are realised by membrane proteins and contribute to a cell's specificity and functionality. The analysis of membrane proteins has shown to be an important part in the understanding of complex biological processes. Genome-wide investigations of membrane proteins have revealed a large number of short, distinct sequence motifs. Results. The in silico analysis of 32 membrane protein families with domains of unknown functions discussed in this study led to a novel approach which describes the separation of motifs by residue-specific distributions. Based on these distributions, the topology structure of the majority of motifs in hypothesised membrane proteins with unknown topology can be predicted. Conclusion. We hypothesise that short sequence motifs can be separated into structure-forming motifs on the one hand, as such motifs show high prediction accuracy in all investigated protein families. This points to their general importance in α-helical membrane protein structure formation and interaction mediation. On the other hand, motifs which show high prediction accuracies only in certain families can be classified as functionally important and relevant for family-specific functional characteristics.

A Quantitative Structure-Activity Relationship and Molecular Modeling Study on a Series of Biaryl Imidazole Derivatives Acting as H+/K+-ATPase Inhibitors

The H+/K+-ATPase or proton pump is a magnesium-dependant enzyme which causes the exchange of a proton against a potassium ion through a membrane. Over activity of this enzyme causes hyperacidity by producing more of hydrochloric acid inside the stomach. This enzyme, therefore, has been found to be a good target for designing compounds to treat hyperacidity. A quantitative structure-activity relationship (QSAR) study has been made on a novel series of biaryl imidazole derivatives acting as H+/K+-ATPase inhibitors. The H+/K+-ATPase inhibition activity of these compounds is found to be significantly correlated with global topological charge indices (GTCIs) and the total polar surface area (TPSA) of the molecules, indicating the involvement of strong electronic interaction between the molecule and the receptor. Based on the correlations obtained, some new H+/K+-ATPase inhibitors are predicted. The docking studies of these predicted compounds exhibit that these compounds will have even better interaction with the receptor than those already marketed. Thus, they can prove more potent drugs for the treatment of hyperacidity.